This invention relates to novel inhibitory peptides and, more particularly, to peptides which inhibit (a) the binding of tissue plasminogen activator (tPA) to human endothelial cells and (b) the inactivation of tPA by plasminogen activator inhibitor-1 (PAI-1).
A considerable body of evidence has accumulated indicating that the ability of an individual to degrade fibrin clots is determined by the ratio of plasminogen activator inhibitor (PAI-1) to tissue plasminogen activator (tPA) found within that individual's plasma. An abnormally high ratio (i.e., an excessive concentration of PAI-1) appears to be a causative factor in a large percentage of patients with serious thromboembolic disease [Nilsson et al., Br. Med. J. 290, 1453-1456 (1985); Jorgensen and Bonnevie-Nielsen, Br. J. Haematol. 65, 175-180 (1987); and Juhan-Vague et al., Thromb. Haemost. 57, 67-72 (1987)]. Elevated levels of PAI-1 have also been associated with coronary heart disease and there is a direct correlation between plasma PAI-1 levels and the probability that a patient who has had a myocardial infarction will have a recurrence [Mehta et al., J. Am. Cell. Cardiol. 9, 263-268 (1987); and Hamsten et al., Lancet 2, 3-9 (1987)].
A number of recent reports have suggested that the release of PAI-1 by platelets at the site of clot formation may lead to localized concentrations of the inhibitor which are much higher than those found elsewhere in the plasma [Kruithof et al., Blood 70, 1645-1653 (1987); Booth et al., J. Clin. Pathol. 38, 825-830 (1985); Sprengers et al., Thromb. Haemost. 55, 325-329 (1986); and Jang et al., Circulation 79, 920-928 (1989)]. As a result, clot lysis by tPA administered therapeutically may be correspondingly less effective. Therapeutically administered tPA may also be lost due to binding to the endothelial cells lining blood vessels. These cells contain a large number of high affinity binding sites for tPA and at least a portion of the sites appear to represent membrane bound PAI-1 [Hajjar et al., J. Clin. Invest. 80, 1712-1719 (1987); Barnathan et al., J. Biol. Chem. 263, 7792-7797(1988); Beebe, Thromb. Res. 46, 241-254 (1987); and Sakata et al., J. Biol. Chem. 263, 1960-1969 (1988)].
Small, synthesizeable molecules which prevent the inactivation of tPA by PAI-1 may provide a means for either improving the efficacy of therapeutically administered tPA or for reducing the tendency of patients with elevated plasma PAI-1 concentrations to form fibrin clots.